The primary overall goal of the proposed research on this entire NCCP grant is to synthesize, evaluate and identify analogs of vitamin D which induce differentiation and inhibit proliferation of leukemia and preleukemia cells without causing hypercalcemia. The starting point in our long term analysis is that the disease of leukemia represents a form of cancer in which an inappropriate block to stem cell differentiation exists, coupled with an enhancement of cell proliferation. Also we know that the vitamin D metabolite 1,25(OH)2D3 is a very potent mediator of stem cell differentiation and clonal proliferation. This PROJECT of the NCCP grant will apply a four-step vitamin D analog screening strategy to generate a profile of biological actions of any given analog (particularly those synthesized by W.H. Okamura of this NCCP team). For Specific Aims are proposed: (1.0) Level A analysis of analogs for primary biological activity relative to 1,25(OH)2D3 receptors in vitro, and stimulation in vivo of intestinal Ca2+ absorption and bone Ca2+ mobilization; (2.0) Level B analysis of the biological activity of selected analogs relative to components of the vitamin D endocrine system including assessment of an analog's ability to inhibit the endogenous production of 1,25(OH)2D3 and alter the metabolism of 25(OH)D3; (3.0) Level C assessment of the therapeutic potential of a small number of selected analogs in an animal model of leukemia (BALB/c mouse plus/minus WEHI-3BD+ cells); and (4.00 Level D for a selected few analogs, determination of their pharmacokinetic properties and structural features necessary to mediate genomic and nongenomic responses.